4-fluoro-ypsilon-(4-methylpiperidino)-butyrophenone and its pharmaceutically acceptable salts

ABSTRACT

THE INVENTION RELATES TO A BASIC KETONE COMPOUND HAVING THE FORMULA:   1-((4-F-PHENYL)-CO-(CH2)3-),4-CH3-PIPERIDINE   AND PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF. THE COMPOUND OF THE INVENTION HAS VALUABLE PHARMACEUTICAL PROPERTIES.

United States Patent 3 816,433 4-FLUORO 'y (4-METHYLPlPERIDINO)-BUTYRO-PHENONE AND ITS PHARMACEUTICALLY ACCEPTABLE SALTS Patented June 11, 1974The compound according to the present invention may be used clinicallyin the treatment of for instance senile confusion and dementia,schizophrenia, mania and for the treatment of hallucinations caused bybrain injuries.

5 The compound of the present invention is in general less 2 3:3 a z andig i iggg gigs? toxic and the effective doses per keg. bodyweight issmaller D g gs gga g g fg gi Malmo, as compared to similar previouslyknown compounds, such No Drawing C(mfimmfiomimpart of application s asthe substituted amino-ketones disclosed in the French 725,134, Apr. 29,1968, which is a continuation-in-part Patent speclficatloh 1, 63 (Bereglet and the of applications Ser. No. 385,058, July 24, 1964, and 10'y-(Z-methylpiperidino)-butyrophenone compounds dis- Ser. No. 536,293,Mar. 22, 1966, all now abandonedclosed in J. Am. Chem. Soc., vol. 68,page 2592 (Piperi- This PP g &:] ,C 0 7 2 73,289 dine Derivatives XVII,Local Anesthetics Derived From 11 ubsti ute er'd'n l US. Cl. 260-293.8 2Claims g Alcoho by S M m and 15 The above-mentioned use of the compoundof the in- ABSTRACT OF THE DISCLOSURE vention is only possible since itdoes not affect the blood pressure which is in contrast to the compoundaccording ggggfggg relates to baslc ketone compougnd hav to the FrenchMedicinal patent No. 1,459 M which differs from the present compoundonly in that it is unsubstituted CHI-C13 in the 4-position of thepiperidine ring.

CH -CH N-(tJHm-COG-F The compound according to the French MedicinalCHPCH/I patent No. 1,459 M has found use primarily as a potent drug forthe treatment of hypertension or as a tranquilizer, andpharmacf'utlcaliy acceptable Salts thereof T Whereas the compoundaccording to the present invention pound of the invention has valuablepharmaceutical propv may be used for relieving a Wide variety of mentalemes' disturbances. It will be obvious that, for a compound to be usedfor relieving mental disturbances, it Will be de- The Prfisent Patentapphcatlon 1S a commuatlon'm'part sired that it does not affect theblood pressure so that it Of the application 5513 725,134 filed on 29,1968 may be used in the required, often massive, doses without which isa continuation-in-part of the applications Ser. any d l i Side ff t385,053 and 536,293. filed on y 24, 1964 and Comparative pharmacologicaltests have been made for Mtlr- 1966, P 2111 three applications beingahahevaluating the properties of the hydrochlorides of the doned.compound according to the present invention and two The Presentinvention relates to ketone homologues thereof, viz. the compounds inwhich the pound, 4-fluOr0-v-(4- Y P P butyrophe' methyl group attachedto the piperidino group is in posi- O havlng the fOHOWlIlg structuralformula: tions 2 and 3 resp., as well as the compound according toCH1-CH1 the French Medicinal patent No. 1,459 M, viz. the cor- CHFCQresponding compound without the methyl group.

cHrC 40 The results of the tests are shown in the table below. and thepharmaceutically acceptable salts thereof. Compound accofdmg t0 thePresent t o The novel compound is a potent central depressant withCompound III the y homologue of Compound anti-convulsant and pronouncedtranquilizing effects when Compound III: the 3-methyl homologue ofcompound I. administered as such or in the form of an acid additionCompound IV: the compound according to the French salt such as thehydrochloride. Even in low doses, proteco Medicinal patent No. 1,459 M.

TABLE Mg./kg.

Potentia- Amphet- Apomortion of the Hypo- Analgesic activity amine phinebarbiturate thermie Climb- Squirrel Condition antagoantagoanaesthesiaeffect, Hotplate Writhing ing test, wheel response nism, nism, ES ED5 0.test, EDsu test, EDI) ED test, ED50 test, ED50 ED50 ED50 2 5 4 2 1 2 2 1s 13 160 28 10 10 5 20 240 50 6 28 10 5 5 5 7 4 11 4 1s 14 2 4 a 9 1o 19tion is achieved against convulsions provoked by electric The varioustests have been carried out in the followshock, strychnine or metrazole.The new compound also ing way: decreases the spontaneous activity oflaboratory animals as (1) The LD values have been determined by givingmeasured in the jiggle cage, the squirrel wheel and the increasing dosesof the compounds to mice and the LD climbing tests. The toxicity of thenew compound is low values are mgs. per kg. which kill 50% of the mice.and its action on the autonomic nervous system is weak. (2) Thepotentiation of the barbiturate anaesthes a has Electro-encephalographicstudies on rabbit show that the 5 been measured in the following way:new compound induces adesynchronization in the cortical Sleeping time,defined as the time during which the electrO-encephalogram, whichprobably is a sign of an animals remained supine, was determined afterintraincreased alertness of the brain. The new compound posvenousinjection of hexobarbital 50 mg./kg. The sleeping sesses a prominentanalgetic activity as measured in the times of mice, pretreatedsubcutaneously with varying writhing test; in low doses it blocks theconditioned avoiddoses of the test compounds (6 mice/dose) 30 minutesance response of rats. The new compound has a strong hypothermicactivity in laboratory animals.

before the hexobarbital injection, were compared with those of untreatedcontrols according to the method of 3 Winter (1948). The sedative dose,ESD, was the dose in mg./ kg. which prolonged the sleeping time fourtimes as compared with the controls.

(3) The hypothermic effect has been measured in the following way: Therectal temperature of mice was determined with a thermocouple, readingsevery 30 minutes. Varying doses of test compound were injected subcutaneously using 6 mice/dose. The experiments, each including 6experimental and 6 control mice, were carried out at a constant roomtemperature (22 C.). The ED was the dose that reduced the bodytemperature 5 C.

(4) The analgetic hot plate test has been carried out in the followingmanner: Thermal pain stimuli have been utilized in different studies ofanalgesic activity. A convenient and rapid screening test is the hotplate method of Woolfe & MacDonald (1944). The test substance wasadministered subcutaneously in graded doses (6 mice/ dose) 30 minutesbefore placing the animals on an iron plate thermostatically controlledat 55 C. The control mice showed active signs of discomfort, e.g.sitting on their hind legs and licking their front paws. ED wascalculated as the dose in mg./kg. at which 50% of the animals did notshow this reaction in seconds.

(5) The analgesic writhing test has been carried out in the followingway: Intraperitoneal injection of irritating substances has been show tocause a special syndrome in mice, which may be abolished byanalgesics--strong, morphine like ones as well as weaker agents of theantipyretic type (Siegmund et al. 1957, 'Eckhardt et al. 1958). Asirritating substance a diluted solution of acetic acid (15 ml./kg. of a0.5% solution) was used. In 100% of the control animals this solutionprovoked a writhing syndrome characterized by intermittent contractionsof the abdomen and trunk and stretching of the hind limbs. The testsubstance was injected subcutaneously in graded doses minutes before theacetic acid (6 mice/dose) and 10 minutes later the animals were observedfor the writhing syndrome during 5 minutes. ED was the dose in mg./kg.at which the writhing syndrome was abolished in 50% of the animals. Thistest was also employed to ascertain whether the analgesic effect of thetested substance was antagonized by nalorphine (subcutaneouslyadministration to 6 animals per dose) with morphine as referencesubstance.

(6) The climbing test has been carried out in the following manner: Themethod was described by Kneip (1960) and Sandberg (1959). Groups of 6mice were put in a rectangular cage with transparent plastic walls and anet floor. Each cage was provided with a net ladder, which permitted theanimals to climb out of the cage, and normally all mice left the cage ina few minutes (high exploring activity in a new environment). The testdrugs were administered subcutaneously in graded doses minutes beforethe animals were put in the cage (one group of 6 mice/dose), and ED wastaken to be the dose in mg./kg. which made 50% of the animals remain inthe cage for 10 minutes.

(7) The squirrel wheel test has been carried out in the followingmanner: A special design of activity wheels, giving the animals freechoice to enter the wheels, was used (Ljungberg 1957, Strom 1964). Onemouse was put in each cage with a revolving drum 15 minutes after asubcutaneous injection of the substances, and the activity, in drumresolutions during one hour, was recorded. Half the animals were givenphysiological saline, while the other half received the test substance.After three days the procedure was repeated, but the groupsinterchanged. Consequently, each animal acted as its own control.Individual quotients of activity and the average values of thesequotients were calculated. 12 mice were employed on each dosage, and theactivity of the test drugs was recorded as ED i.e. the dose in mg./kg.by which a 50% decrease of activity Was obtained.

(8) The condition response test has been carried out in the followingmanner: The test was in all essentials performed according to themodification of Jacobsen & Sonne (1955). The apparatus consisted of arectangular transparent plastic cage, divided into two compartments by anon-transparent wall with a opening through which the animals could movefreely. The floor was a grid made of stainless steel rods. By means oftwo switches an electrice shock could be given through the grid of eachcompartment. Outside the cage of buzzer was mounted.

Rats were trained to avoid the electric shock (unconditioned stimulusUS)by escaping from one compartment to the other when a buzzer signal(conditioned stimulusCS) was given. When they responded to the CS aconditioned response (CR) was considered to have been elicited.

The specific blocking action on the CR was tested by administering thetest drug subcutaneously in graded doses to 10 rats per dose level.After 2 hours the rats were placed in the cage, and the reaction to CSand US was observed. Ifthe animals failed to escape to the othercompartment after CS but reacted to the US, a specific blocking actionon the CR was considered to have been obtained. ED was the dose inmg./kg. at which this occurred in 50% of the animals two hours after theadministration of the drug.

(9) The amphetamine antagonism has been measured by determining thequantities of the tested substances necessary for compensating theeffect of amphetamine on the central nervous system causing stereotypyas a consequence of the dopamine liberating action of amphetamine. EDwas the dose in mg./kg. at which this stereotypy was abolished in 50% ofthe animals.

(10) The determination of the apomorphine antagonism has been carriedout as described in the article of J. A. Christensen, S. Hernestam, J.B. Lassen and N. Sterner in Acta Pharmacologica et Toxicologica, 1965,vol. 23, pages 109-132.

This test has been used by many for the purpose of correlating structureand neuroleptic potency [P. A. J. Janssen et a1. Arzneimittelforschung9, 765 (1959); ibid 10, 1003 1960)]. The reason is that we know the siteof action of apomorphine in the brain and that all neuroleptics used areknown to prevent apomorphine-induced vomiting by acting on the samesite, namely on the chemoemetic trigger zone which is a very smallreceptor located in the area postrema at the floor of the fourthventricle. When stimulated by apomorphine, the chemoemetic trigger zonewill trigger the vomiting centre and hereby the whole emetic process.

The action of a neuroleptic in this test is thought to be as follows:After administration, the neuroleptic drug circulates in the bloodstream and a small amount penetrates into the chemoemetic trigger zonevia a vascular foot of a reddish fluorescent astrocyte which constitutesthe local blood-brain barrier. The drug crosses the cell body of theastrocyte, penetrates into the synaptic cleft of a dopamine-containingadrenergic neurone and forms a monolayer on the surface of the membranessurrounding the synaptic cleft. This surface is rich in GABA-receptorsand the neuroleptic drug will complete with GABA for occupying thesereceptors, thus making them inaccessible for l-glutamic acid. By thusexerting a GABA-like action, the neuroleptic drug decreases thepermeability of the post synaptic membrane surrounding thetransmitterreceptor. As a consequence of this action, the access ofreleased transmitter-molecules of dopamine to their receptors isprevented and the nervous transmission process is blocked. When noneuroleptic molecules are present, dopamine is allowed to act as anormal transmitter, it crosses the postsynaptic membrane, reaches itsreceptor site, transmits the nervous impulse to the vomiting centre andthus triggers the emetic process. With neuroleptic drugs present, thisnormal triggering process is blocked at the postsynaptic membrane level,dopamine being prevented from reaching its receptor site.

The experiments show that the compound of the present invention has ahigher LD value, it is less toxic than the related compounds except the3-methyl homologue; further, the ED values of the present compound arelower than the corresponding values of the related compounds, i.e. thecompound according to the invention is more pharmaceutically active, andfinally, the therapeutic indices (LD /ED are higher for the presentcompound than for the comparative compounds which diminishes the risk ofany toxic effect in the practical use of the compound.

The novel compound or its acid addition salts such as the hydrochlorideis usually administered per as, for instance in the form of pills ortablets.

For many purposes a suitable clinical does is between and 500 mgs.(calculated as the free base) administered three or four times daily.Naturally, the doses should be adjusted in accordance with thecondition, age and weight of the patient.

The invention includes compositions suitable for administration to humanbeings comprising the new com pound of the invention or acid additionsalts thereof, especially the hydrochlorides, together with an inertdiluent or carrier or dissolved in water for injection. Suchcompositions may also comprise other active substances.

Tablets may be made by compounding one of the new compounds or an acidaddition salt thereof with customary carriers and adjuvants. Thefollowing is a suitable tablet formation:

2.5 gms. of the hydrochloride of 4-fiuoro-y-(4-methylpiperidino)-butyrophenone 9 gms. of potato starch 1 gm. of colloidal silica 2.5gms. of a 5% aqueous solution of gelatine 2 gms. of talcum 0.2 gms. ofmagnesium stearate.

This mixture is made up into 100 tablets, each, therefore, containing 25mgs., of the active component.

The compound of the invention may be prepared by reacting a4methyl-piperidine with -halogeno-p-fluorobutyrophenone at an elevatedtemperature and in the presence of an acid binding agent which may beprovided by using an excess of the 4-methyl-piperidine, preferably onemolecular proportion in excess.

The heating is preferably made in the presence of potassium iodide so asto avoid undesired side reactions. The reaction may be performed in asealed tube and the reaction medium may be an inert solvent or diluentsuch as a hydrocarbon e.g. toluene. With the use of a reaction mediumthe yields are improved and the reaction times are decreased.

The reaction product is recovered from the reaction mixture in aconventional manner, such as by distillation. The acid addition saltsare also prepared conventionally, such as by dissolving the base inether and precipitating it e.g. in the form of the hydrochloride byadding hydrogen chloride.

Suitable pharmaceutically acceptable acids are mineral acids such ashydrochloric acid, sulphuric acid, etc., and organic acids such assuccinic acid, maleic acid, malonic acid, palmitic acid, etc.

The following example illustrates the preparation of the compound of theinvention.

EXAMPLE A solution or dispersion consisting of 20.1 gms. (0.1 I

mole) of 'y-chloro-pdluorobutyrophenone, 19.8 gms. (0.2 mole) of4-methyl-piperidine and 0.1 gm. of potassium iodide in 150 mls. tolueneis heated in a sealed glass tube for 15 hours at -1 10 C. The potassiumiodide and the 4-methyl-piperidine hydrochloride formed in the reactionare separated by filtration and the solvent removed from the filtrate byevaporation in vacuum on a steam bath. The residue is distilled and thefraction obtained at -125 C. and at a pressure lower than .1 mm. Hg iscollected. The base is dissolved in ether and the 4-fluoro-'y-(4-methyl-piperidino)-butyrophenone precipitated as thehydrochloride. The reaction product is purified by recrystallization inethanol/ ether.

Yield 22.0 gms. (73% of theory). Melting point 209- 211 C.

Analysis, percent Calculated Actual What we claim is: 1. Apharmaceutically active basic kctone having the formula:

CHg-CH;

UNITED STATES PATENTS 1,915,334 6/ 1933 Salzberg et a1 260-243 FOREIGNPATENTS 1,459 M 8/ 1962 France 260293.8

OTHER REFERENCES Pharmacology and Therapeutics, 6th ed. (1965), pp. 36and 37, Grollman. Acta Pharmacol. et

toxicol. (1965), 23: 109 and 128, Christensen et al.

HENRY -R. IILES, Primary Examiner S. D. WINTERS, Assistant Examiner US.Cl. X.R. 424-267

